Bruno C Medeiros, MD

Associate Professor of Medicine (Hematology) at the Stanford University Medical Center

Medicine - Hematology

Bio

Bio

Bruno C. Medeiros, MD is associate professor of medicine and director of the inpatient hematology service. He is also director of Cancer Center ITA services at Stanford Comprehensive Cancer Center. Dr. Medeiros graduated from the Universidade Federal do Parana with a medical degree, in 1998. He completed his post-graduate training at the University of Colorado in Denver and the Princess Margaret Hospital in Toronto (Acute leukemia fellowship). Dr. Medeiros? clinical interests include management of advanced hematologic malignancies, including AML, ALL, MDS and CML. His clinical research interest focuses on the development of novel therapeutic regimens for patients with acute leukemia, with special interest in the development of novel therapeutic strategies for patients with acute myeloid leukemia. He is the leader in several institutional investigator initiated clinical trials, active investigator in collaborative multi-institutional clinical studies and an active member of the SWOG acute leukemia panel. Dr. Medeiros has authored more than 120 peer-reviewed manuscripts. Dr. Medeiros has served as the track leader for ASCO meeting Leukemia, Myelodysplasia and Transplantation scientific review subcommittee, he functions as the Associate Editor of the Leukemia Panel for Cancer.Net, he is a member of the editorial board for Leukemia Research and serves as a reviewer for several specialized journals, such as Blood, Leukemia, Haematologica and Cancer, among others.

Contact

Research & Scholarship

Current Research and Scholarly Interests

My clinical activities combine the development of novel therapeutic modalities, translational research activities and epidemiological study of acute leukemia. My special focus is on the development of better, patient tailored therapies for young and elderly patients with acute leukemia.

Clinical Trials

To confirm the efficacy of CPX-351 compared to 7+3 as first line therapy in elderly patients
(60-75 yrs) with high risk (secondary) Acute Myeloid Leukemia. The primary efficacy endpoint
will be overall survival.

Stanford is currently not accepting patients for this trial.For more information, please contact Marlene Zuraek, (650) 736 - 4031.

RATIONALE: Monoclonal antibodies, such as epratuzumab, can block cancer growth in different
ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and
help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such
as cytarabine and clofarabine, work in different ways to stop the growth of cancer cells,
either by killing the cells or by stopping them from dividing. Giving epratuzumab together
with cytarabine and clofarabine may kill more cancer cells.
PURPOSE: This phase II trial is studying the side effects and how well giving epratuzumab
together with cytarabine and clofarabine works in treating patients with relapsed or
refractory acute lymphoblastic leukemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Nini Estevez, (650) 725 - 4041.

This study has a phase 1 and a phase 2 component.
In phase 1, the objective is to determine the maximum tolerated dose (MTD) of lenalidomide
when after azacitidine.
In phase 2, the objective is to determine the efficacy of the combination treatment.

Stanford is currently not accepting patients for this trial.For more information, please contact Leonel Gallegos, (650) 723 - 2781.

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer
cells, either by killing the cells or by stopping them from dividing. Giving more than one
drug (combination chemotherapy) may kill more cancer cells.
PURPOSE: This phase II trial is studying how well combination chemotherapy works in treating
young patients with newly diagnosed acute lymphoblastic leukemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Joselene Sipin-Sayno, (650) 736 - 8113.

Phase I Bortezomib (VELCADE) in Combo With Pralatrexate in Relapsed/Refractory MMNot Recruiting

The purpose of this trial is to find out the maximum tolerated dose (MTD) of bortezomib
(VELCADE) in combination with pralatrexate in patients with previously treated multiple
myeloma, AL amyloid and Waldenstroem's macroglobulinemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Ying Hao, 650-723-0646.

Study to Determine the Maximum Tolerated Dose and Evaluate the Efficacy and Safety of CEP-18770 (Delanzomib) in Patients With Relapsed Multiple Myeloma Refractory to the Most Recent TherapyNot Recruiting

The primary objective for part 1 of the study is to determine the maximum tolerated dose
(MTD) of CEP-18770 in patients with relapsed and refractory multiple myeloma. The primary
objective for part 2 is to evaluate the antitumor activity of CEP-18770 in patients treated
at the MTD.

Stanford is currently not accepting patients for this trial.For more information, please contact Leonel Gallegos, (650) 723 - 2781.

Safety Study of CAT-8015 Immunooxin in Patients With HCL With Advance DiseaseNot Recruiting

RATIONALE: The CAT-8015 immunotoxin can bind tumor cells and kill them without harming normal
cells. This may be an effective treatment for hairy cell leukemia(HCL) that has not responded
to chemotherapy, surgery or radiation therapy.
PURPOSE: Phase I dose escalation study to determine the maximum tolerated dose of CAT-8015
immunotoxin in treating patients who have hairy cell leukemia (HCL) that has not responded to
treatment.

Stanford is currently not accepting patients for this trial.For more information, please contact Michelle Takahashi, (650) 736 - 4032.

Acute myeloid leukemia (AML) is a cancer of the bone marrow that mostly affects older adults.
Even with the best chemotherapy, two-year disease-free survival is achieved in a minority of
patients. Bone marrow transplantation from a sibling donor may improve cure rates; however,
patients over 50 years of age have a high risk of complications and therefore generally are
excluded from this treatment option. Recently our group developed a transplantation strategy
for older cancer patients that protects against transplant-associated complications, yet does
not interfere with the ability of the transplanted donor cells to destroy cancer cells. With
this new method, we can now safely evaluate transplantation as a curative therapy for AML
patients over the age of 50. We have assembled clinical and scientific researchers throughout
the state of California to study and compare bone marrow transplantation using our new
approach with the best standard of care chemotherapy in AML patients over the age of 50. The
results of this study have the potential to establish a new treatment standard that will
improve survival of older AML patients.

Stanford is currently not accepting patients for this trial.For more information, please contact BMT Referrals, 650-725-1647.

The overall aim of this study is to assess the efficacy and safety of AS1411, over a range of
doses, when combined with cytarabine, in the treatment of patients with primary refractory or
relapsed acute myeloid leukemia (AML).

Stanford is currently not accepting patients for this trial.For more information, please contact Richa Rajwanshi, (650) 736 - 4031.

The main objective of this study is to learn which sapacitabine treatment is more likely to
keep the cancer in check for at least one year in AML patients who are at least 70 years of
age or older and in MDS patients who are at least 60 years of age.

Stanford is currently not accepting patients for this trial.For more information, please contact Michelle Takahashi, (650) 736 - 4032.

RATIONALE: Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different
ways to stop the growth of cancer cells, either by killing the cells or by stopping them from
dividing. Pravastatin may stop the growth of cancer cells by blocking some of the enzymes
needed for cell growth. Pravastatin may also help idarubicin and cytarabine work better by
making cancer cells more sensitive to the drugs. Giving idarubicin and cytarabine together
with pravastatin may kill more cancer cells.
PURPOSE: This phase II trial is studying how well giving idarubicin and cytarabine together
with pravastatin works in treating patients with relapsed acute myeloid leukemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Joselene Sipin-Sayno, 650-736-8113.

The purpose of this study is to compare the effects, good and/or bad, of a standard
chemotherapy regimen for AML that includes the drugs daunorubicin and cytarabine combined
with or without midostaurin (also known as PKC412), to find out which is better. This
research is being done because it is unknown whether the addition of midostaurin to
chemotherapy treatment is better than chemotherapy treatment alone. Midostaurin has been
tested in over 400 patients and is being studied in a number of illnesses, including AML,
colon cancer, and lung cancer. Midostaurin blocks an enzyme, produced by a gene known as
FLT3, that may have a role in the survival and growth of AML cells. Not all leukemia cells
will have the abnormal FLT3 gene. This study will focus only on patients with leukemia cells
with the abnormal FLT3 gene.

Stanford is currently not accepting patients for this trial.For more information, please contact Leonel Gallegos, (650) 723 - 2781.

Extension Study of Idelalisib for Patients With Chronic Lymphocytic Leukemia Who Participated in GS-US-312-0116Not Recruiting

This study (GS-US-312-0117) is a multicenter, 2-arm, double-blind, parallel-group extension
study that is a companion study to Study GS-US-312-0116, to evaluate the effect of idelalisib
on the onset, magnitude, and duration of tumor control.

Stanford is currently not accepting patients for this trial.For more information, please contact Tessa Hunter, (650) 736 - 4032.

We hope to learn more about the clinical efficacy of bortezomib in T-cell prolymphocytic
leukemia. Patients will be selected as a possible participant in this study because they have
a bone marrow disorder known as T-cell prolymphocytic leukemia (T-cell PLL) which does not
tend to respond well to conventional treatment with chemotherapy.

Stanford is currently not accepting patients for this trial.For more information, please contact Richa Rajwanshi, (650) 736 - 4031.

The purpose of this study is to evaluate the efficacy and safety of idelalisib in patients
with previously treated indolent Non-Hodgkin Lymphoma (iNHL) that is refractory both to
rituximab and to alkylating-agent-containing chemotherapy. The primary objective will be to
assess the overall response rate.
Eligible patients will initiate oral therapy with idelalisib at a starting dose of 150 mg
taken twice per day. Treatment with idelalisib can continue in compliant patients as long as
the study is still ongoing and the patients appear to be benefiting from treatment with
acceptable safety.

Stanford is currently not accepting patients for this trial.For more information, please contact Tessa St.Rose, (650) 736 - 4032.

A Study of Clofarabine and Cytarabine for Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)(CLASSIC I)Not Recruiting

Clofarabine (injection) is approved by the Food and Drug Administration (FDA) for the
treatment of pediatric patients 1 to 21 years old with relapsed acute or refractory
lymphoblastic leukemia (ALL) who have had at least 2 prior treatment regimens.
There is no recommended standard treatment for relapsed or refractory acute myelogenous
leukemia in older patients. Cytarabine is the most commonly used drug to treat these
patients. This study will determine if there is benefit by combining clofarabine with
cytarabine. Patients will be randomized to receive up to 3 cycles of treatment with either
placebo in combination with cytarabine or clofarabine in combination with cytarabine.
Randomization was stratified by remission status following the first induction regimen (no
remission [i.e., CR1 = refractory] or remission <6 months vs CR1 = remission ?6 months). CR1
is defined as remission after first pre-study induction regimen. The safety and tolerability
of clofarabine in combination with cytarabine and cytarabine alone will be monitored
throughout the study.

Stanford is currently not accepting patients for this trial.For more information, please contact Richa Rajwanshi, (650) 736 - 4031.

This phase I trial studies the side effects and the best dose of lenalidomide when given
together with combination chemotherapy in treating patients with relapsed or refractory acute
myeloid leukemia. Lenalidomide may stop the growth of acute myeloid leukemia by blocking
blood flow to the cancer. Drugs used in chemotherapy, such as mitoxantrone hydrochloride,
etoposide, and cytarabine, work in different ways to stop the growth of cancer cells, either
by killing the cells or by stopping them from dividing. Giving lenalidomide and combination
chemotherapy may be an effective treatment for acute myeloid leukemia.

Azacitidine With or Without Lenalidomide or Vorinostat in Treating Patients With Higher-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic LeukemiaNot Recruiting

This randomized phase II/III trial studies how well azacitidine works with or without
lenalidomide or vorinostat in treating patients with higher-risk myelodysplastic syndromes or
chronic myelomonocytic leukemia. Drugs used in chemotherapy, such as azacitidine, work in
different ways to stop the growth of cancer cells, either by killing the cells, stopping them
from dividing, or by stopping them from spreading. Lenalidomide may stop the growth of cancer
cells by stopping blood flow to the cancer. Vorinostat may stop the growth of cancer cells by
blocking some of the enzymes needed for cell growth. It is not yet known whether azacitidine
is more effective with or without lenalidomide or vorinostat in treating myelodysplastic
syndromes or chronic myelomonocytic leukemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Joselene Sipin-Sayno, 650-736-8113.

Cytarabine and Daunorubicin Hydrochloride or Idarubicin and Cytarabine With or Without Vorinostat in Treating Younger Patients With Previously Untreated Acute Myeloid LeukemiaNot Recruiting

This randomized phase III trial studies cytarabine and daunorubicin hydrochloride or
idarubicin and cytarabine with or without vorinostat to see how well they work in treating
younger patients with previously untreated acute myeloid leukemia. Drugs used in
chemotherapy, such as cytarabine, daunorubicin hydrochloride, idarubicin, and vorinostat,
work in different ways to stop the growth of cancer cells, either by killing the cells,
stopping them from dividing, or by stopping from spreading. Giving more than one drug
(combination chemotherapy) and giving the drugs in different doses and in different
combinations may kill more cancer cells. It is not yet known which combination chemotherapy
is more effective in treating acute myeloid leukemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Joselene Sipin-Sayno, 650-736-8113.

This phase 2 trial studies how well ixazomib(MLN9708) works in treating patients with
relapsed or refractory acute myeloid leukemia. Ixazomib may stop the growth of cancer cells
by blocking some of the enzymes needed for cell growth.

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, 650-723-1269.

An Extension Study for Subjects Who Are Deriving Benefit With Idelalisib (GS-1101; CAL-101) Following Completion of a Prior Idelalisib StudyNot Recruiting

This is a long-term safety extension study of idelalisib (GS-1101; CAL-101) in patients with
hematologic malignancies who complete other idelalisib studies. It provides the opportunity
for patients to continue treatment as long as the patient is deriving clinical benefit.
Patients will be followed according to the standard of care as appropriate for their type of
cancer. The dose of idelalisib will generally be the same as the dose that was administered
at the end of the prior study, but may be titrated up to improve clinical response or down
for toxicity. Patients will be withdrawn from the study if they develop progressive disease,
unacceptable toxicity related to idelalisib, or if they no longer derive clinical benefit in
the opinion of the investigator.

Stanford is currently not accepting patients for this trial.For more information, please contact Nini Estevez, 650-725-4041.

Study of MLN4924 Plus Azacitidine in Treatment-Naïve Patients With Acute Myelogenous Leukemia (AML) Who Are 60 Years or OlderNot Recruiting

This study is an open-label, multicenter, phase 1b, dose-escalation study of MLN4924 in
combination with azacitidine in adult patients with AML. The patient population will consist
of patients 60 years of age or older, previously diagnosed with World Health
Organization(WHO)-defined AML, who are unlikely to benefit from standard induction therapy
and who have not received definitive treatment for AML or prior treatment with azacitidine or
decitabine.

Stanford is currently not accepting patients for this trial.For more information, please contact Marlene Zuraek, (650) 736-4031.

This study is to evaluate the efficacy and safety of simtuzumab (GS-6624) on bone marrow
fibrosis either alone or in combination with ruxolitinib in participants with Primary
myelofibrosis (PMF) and Post Polycythemia Vera or Post Essential Thrombocythemia
Myelofibrosis (ET/PV MF).
The study is designed as a two stage trial. In the stage 1, patients will be randomized into
two cohorts to receive either 200 or 700 mg of study drug. In the stage 2, patients on
ruxolitinib will be randomized to receive either 200 or 700 mg of study drug.

Stanford is currently not accepting patients for this trial.For more information, please contact Andrea Linder, (650) 725 - 4047.

This phase I trial studies the MEK inhibitor MEK162 to see if it is safe in patients when
combined with idarubicin and cytarabine. MEK inhibitor MEK162 may stop the growth of cancer
cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy,
such as idarubicin and cytarabine, work in different ways to stop the growth of cancer cells,
either by killing the cells or by stopping them from dividing. Giving MEK inhibitor MEK162,
cytarabine, and idarubicin may be an effective treatment for acute myeloid leukemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Jack C. Taw, 650-723-2781.

Efficacy and Safety of Midostaurin in Patients With Aggressive Systemic Mastocytosis or Mast Cell LeukemiaNot Recruiting

This study will investigate if the drug midostaurin taken orally twice daily is effective and
safe in treating patients with aggressive systemic mastocytosis or mast cell leukemia with or
without an additional hematological neoplasm.

Stanford is currently not accepting patients for this trial.For more information, please contact Andrea Linder, (650) 725 - 4047.

The purpose of this study is to determine the safety and effectiveness of pracinostat when
combined with azacitadine for patients who are 65 years of age or older and have Acute
Myelogenous Leukemia (AML)

Stanford is currently not accepting patients for this trial.For more information, please contact Leilani Hong Lien, 650-725-0437.

This phase II clinical trial studies how well liposomal cytarabine-daunorubicin CPX-351
(CPX-351) works in treating patients with relapsed or refractory acute myeloid leukemia or
myelodysplastic syndrome. Drugs used in chemotherapy, such as liposomal
cytarabine-daunorubicin CPX-35, work in different ways to stop the growth of cancer cells,
either by killing the cells or by stopping them from dividing.

This randomized clinical trial studies liposomal cytarabine-daunorubicin CPX-351 in treating
patients with untreated myelodysplastic syndrome or acute myeloid leukemia. Drugs used in
chemotherapy, such as liposomal cytarabine-daunorubicin CPX-351, work in different ways to
stop the growth of cancer cells, either by killing the cells, by stopping them from dividing,
or by stopping them from spreading.

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, 650-723-2781.

This phase I trial studies the side effects and best dose of ibrutinib when given together
with idarubicin and cytarabine in treating patients with acute myeloid leukemia that has
returned after a period of improvement or has not responded to previous treatment. Ibrutinib
may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop
the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
stopping them from spreading. Giving ibrutinib together with idarubicin and cytarabine may
kill more cancer cells.

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, 650-723-2781.

Evaluating the Safety of Long Term Dosing of Romiplostim (Formerly AMG 531) in Thrombocytopenic Subjects With Myelodysplastic Syndromes (MDS)Not Recruiting

This is an open label extension study of romiplostim for treatment of thrombocytopenia
(platelet count ? 50 x 10^9/L) in MDS subjects. The study is designed to assess the long-term
safety of treatment with romiplostim, as measured by incidence of overall adverse events, the
incidence of bleeding events, the utilization of platelet transfusions, and the duration of
platelet response. The study will further describe the time to disease progression to acute
myeloid leukemia (AML) and survival.

Stanford is currently not accepting patients for this trial.For more information, please contact Mai Tran, (650) 723 - 8594.

This phase II trial studies the side effects and how well midostaurin works in treating older
patients with acute myeloid leukemia with change in genetic material post-hematopoietic cell
transplantation. Midostaruin may stop the growth of cancer cells by blocking some of the
enzymes needed for cell growth. Giving midostaruin post-transplant may improve patient
outcomes.

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, 650-723-2781.

This study will test an experimental combination of the drugs Mylotarg and 5-azacitidine in
the hopes of finding a treatment that may be effective against Acute Myeloid Leukemia that
has come back after treatment.

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, (650) 723 - 2781.

A Study Being Conducted at Multiple Locations to Compare Safety and Efficacy of Three Different Regimens; (1) High-Dose Lenalidomide; (2) Lenalidomide + Azacitidine; or (3) Azacitidine in Subjects ? 65 Years With Newly-Diagnosed Acute Myeloid LeukemiaNot Recruiting

The study aim is to compare safety and efficacy of high-dose lenalidomide regimen, sequential
azacitidine and lenalidomide and an azacitidine in persons ?65 years with newly-diagnosed
acute myeloid leukemia (AML).

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, (650) 723 - 2781.

The purpose of the study is to first determine if Temozolomide plus Vorinostat in combination
can control relapsed or refractory AML and determine if this combination can be safely taken.
The study will look at the side effects of the Temozolomide plus Vorinostat in combination
and whether the treatment schedule is tolerated.

Stanford is currently not accepting patients for this trial.For more information, please contact Diana Dobbs, 650-736-6295.

This phase II trial is studying the side effects of giving azacitidine together with
gemtuzumab ozogamicin to see how well it works in treating older patients with previously
untreated acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in
different ways to stop the growth of cancer cells, either by killing the cells or by stopping
them from dividing. Azacitidine may also stop the growth of cancer cells by blocking some of
the enzymes needed for cell growth. Monoclonal antibodies, such as gemtuzumab ozogamicin, can
block cancer growth in different ways. Some block the ability of cancer cells to grow and
spread. Others find cancer cells and help kill them or carry cancer-killing substances to
them. Giving azacitidine together with gemtuzumab ozogamicin may kill more cancer cells.

Stanford is currently not accepting patients for this trial.For more information, please contact Joselene Sipin-Sayno, (650) 736 - 8113.

Extension Study Evaluating the Long Term Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET)Not Recruiting

This extension protocol to the core study CCL09101 allows patients who have tolerated the
drug and derived a clinical benefit, to continue to receive treatment beyond the 9 cycles of
the core protocol. Long term safety and efficacy of CYT387 will be evaluated.

Stanford is currently not accepting patients for this trial.For more information, please contact Andrea Linder, (650) 725 - 4027.

Bortezomib and Dexamethasone With or Without Lenalidomide in Treating Patients With Multiple Myeloma Previously Treated With DexamethasoneNot Recruiting

This randomized phase III trial compares bortezomib, dexamethasone, and lenalidomide with
bortezomib and dexamethasone to see how well they work in treating patients with multiple
myeloma previously treated with dexamethasone. Bortezomib may stop the growth of cancer cells
by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as
dexamethasone, work in different ways to stop the growth of cancer cells, either by killing
the cells or by stopping them from dividing. Lenalidomide may stimulate the immune system in
different ways and stop cancer cells from growing. It is not yet known whether giving
bortezomib and dexamethasone is more effective with or without lenalidomide in treating
multiple myeloma.

Stanford is currently not accepting patients for this trial.For more information, please contact Nancy Mori, (650) 724 - 0201.

This study seeks to (i) determine a safe and tolerated dose of CYT387 given to patients with
PMF, post-PV or post-ET and, (ii) assess the effectiveness of orally-administered CYT387 as a
treatment for PMF, post-PV or post-ET.

Stanford is currently not accepting patients for this trial.For more information, please contact Andrea Linder, (650) 725 - 4047.

The purpose of this study is to evaluate the safety of lenalidomide and to define the maximum
tolerated escalation dose level (MTEDL) when administered by a stepwise dose-escalation
schedule in subjects with relapsed or refractory B-cell CLL.

Stanford is currently not accepting patients for this trial.For more information, please contact Michelle Takahashi, (650) 736 - 4032.

The purpose of this study is to test the safety of vorinostat (Zolinza) and azacitidine
(Vidaza) when combined with gemtuzumab ozogamicin (GO) at different dose levels. These drugs
increase the effect of GO against leukemia cells in the test tube, but we don't know yet
whether they also increase the anti-leukemia effect of GO in people.

Stanford is currently not accepting patients for this trial.For more information, please contact Leonel Gallegos, (650) 723 - 2781.

This study will be conducted to assess the maximum tolerated dose (MTD) of panobinostat given
3 times a week (administered on weeks 2 and 3 of a 4 week cycle) in combination with
induction chemotherapy (idarubicin and cytarabine) in newly diagnosed patients with a
cytopathologically confirmed diagnosis of high-risk AML, and to investigate the safety of the
combination in this regimen.

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, (650) 723 - 2781.

An open-label, multicenter, phase 1, dose escalation study of MLN4924 in adult patients with
acute myelogenous leukemia (AML), high-grade myelodysplastic syndrome (MDS). The patient
population will consist of adults previously diagnosed with AML including high-grade MDS for
which standard curative, life-prolonging treatment does not exist or is no longer effective.

Stanford is currently not accepting patients for this trial.For more information, please contact Leonel Gallegos, (650) 723 - 2781.

A Study of Idelalisib and Rituximab in Elderly Patients With Untreated CLL or SLLNot Recruiting

This study is to evaluate the safety and clinical activity of idelalisib alone and in
combination with rituximab in patients with CLL or SLL.
This Phase 2 study will be the first time that idelalisib is administered to previously
untreated patients with hematologic malignancies. Idelalisib has demonstrated clinical
activity as a single agent in relapsed or refractory CLL and SLL with acceptable toxicity,
which supports its evaluation in previously untreated patients. The study population is
limited to patients over 65 years of age because younger patients are generally appropriate
for standard immunochemotherapy regimens that are highly active. Since the mechanism of
action of idelalisib is distinct from rituximab, it is hypothesized that the combination will
be more active than either agent alone. This study will establish initial safety and clinical
activity of idelalisib in combination with rituximab in patients with CLL or SLL. Cohort 2 of
this study will establish safety and clinical activity of idelalisib alone in subjects with
untreated CLL or SLL.

Stanford is currently not accepting patients for this trial.For more information, please contact Nini Estevez, (650) 725 - 4041.

The purpose of the trial is to study how the elderly patients who have previously undergone
treatment for acute myeloid leukemia and high-rRisk myelodysplastic syndromes, respond to a
combined treatment with azacitidine and lenalidomide.

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, 650-723-2781.

Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid LeukemiaNot Recruiting

This randomized phase II trial studies azacitidine with or without entinostat to see how well
they work compared to azacitidine alone in treating patients with myelodysplastic syndromes,
chronic myelomonocytic leukemia, or acute myeloid leukemia. Drugs used in chemotherapy, such
as azacitidine, work in different ways to stop the growth of cancer cells, either by killing
the cells, by stopping them from dividing, or by stopping them from spreading. Entinostat may
stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Giving azacitidine together with entinostat may work better in treating patients with
myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Mai Tran, (650) 723 - 8594.

This phase II trial is studying the side effects of giving combination chemotherapy together
with or without donor stem cell transplant and to see how well it works in treating patients
with acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop
the growth of cancer cells, either by killing the cells or by stopping them from dividing.
Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving
chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the
growth of cancer cells. It also stops the patient's immune system from rejecting the donor's
stem cells. The donated stem cells may replace the patient's immune cells and help destroy
any remaining cancer cells (graft-versus-tumor effect).

Stanford is currently not accepting patients for this trial.For more information, please contact Vani Jain, (650) 725 - 5459.

The purpose of this study is to evaluate the effect of Romiplostim (AMG 531) on the incidence
of clinically significant thrombocytopenic events (grade 3 or 4 and/or receipt of platelet
transfusions) in subjects with low or intermediate risk Myelodysplastic Syndrome (MDS)
receiving hypomethylating agents. It is hypothesized that Romiplostim administration, at the
appropriate dose and schedule, will result in reduction in the incidence of clinically
significant thrombocytopenic events in low or intermediate risk MDS subjects receiving
hypomethylating agents.

Stanford is currently not accepting patients for this trial.For more information, please contact Mai Tran, (650) 723 - 8594.

This is a Phase II, open-label, non-randomized study to evaluate the safety, efficacy, and
pharmacokinetics of tamibarotene in adult patients with relapsed or refractory acute
promyelocytic leukemia (APL) following treatment with all-trans-retinoic acid (ATRA) and
arsenic trioxide (ATO). Patients must have received and failed therapy with ATRA and ATO.
Treatment may have been administered either as combination therapy or sequentially as single
agents. Patients who are intolerant to either drug are eligible for this study.

Stanford is currently not accepting patients for this trial.For more information, please contact Michelle Takahashi, (650) 736 - 4032.

This Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effect of
idelalisib in combination with rituximab on the onset, magnitude, and duration of tumor
control in participants previously treated for chronic lymphocytic leukemia (CLL). Eligible
patients will be randomized with a 1:1 ratio into 1 of the 2 treatment arms to receive either
idelalisib plus rituximab or placebo plus rituximab. Participants who are tolerating primary
study therapy but experience definitive CLL progression are eligible to receive active
idelalisib therapy in the extension study, GS-US-312-0117.

Stanford is currently not accepting patients for this trial.For more information, please contact Tessa Hunter, (650) 736 - 4032.

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer
cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies,
such as gemtuzumab, can block cancer growth in different ways. Some find cancer cells and
help kill them or carry cancer-killing substances to them. Others interfere with the ability
of cancer cells to grow and spread. Gemtuzumab may also stop the growth of promyelocytic
leukemia by blocking blood flow to the cancer. Giving gemtuzumab together with combination
chemotherapy may be more effective in treating promyelocytic leukemia.
PURPOSE: This phase II trial is studying how well giving gemtuzumab together with combination
chemotherapy works in treating patients with previously untreated promyelocytic leukemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Nini Estevez, (650) 725 - 4041.

Abstract

Background Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. Methods We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. Results A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. Conclusions The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).

Abstract

Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation, and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (TCA, also called the 'citric acid' or Krebs) cycle. Both IDH2 and IDH1 (localized in the cytoplasm) proteins catalyze the oxidative decarboxylation of isocitrate to ?-ketoglutarate (?-KG). Mutant IDH enzymes have neomorphic activity and catalyze reduction of ?-KG to the (R) enantiomer of 2-hydroxyglutarate ([R]-2-HG), which is associated with DNA and histone hypermethylation, altered gene expression, and blocked differentiation of hematopoietic progenitor cells. The prognostic significance of mutant IDH (mIDH) is controversial but appears to be influenced by co-mutational status and the specific location of the mutation (IDH1-R132, IDH2-R140, IDH2-R172). Treatments specifically or indirectly targeted to mIDH are currently under clinical investigation; these therapies have been generally well tolerated, and when used as single agents, have shown promise for inducing responses in some mIDH patients when used as first-line treatment, or in relapsed or refractory, AML or MDS. Use of mIDH inhibitors in combination with drugs with non-overlapping mechanisms of action is especially promising, as such regimens may address the clonal heterogeneity and the multifactorial pathogenic processes involved in mIDH myeloid malignancies. Advances in mutational analysis have made testing more rapid and convenient, and less expensive; such testing should become part of routine diagnostic workup and repeated at relapse to identify patients who may benefit from treatments that target mIDH.Leukemia accepted article preview online, 10 October 2016. doi:10.1038/leu.2016.275.

Abstract

Clinical trials are critical to improve AML treatment. It remains, however, unclear if clinical trial participation per se affects prognosis and to what extent the patients selected for trials differ from those of patients receiving intensive therapy off-trial.We conducted a population-based cohort study of newly diagnosed Danish AML patients treated with intensive chemotherapy between 2000-2013. We estimated accrual rates and compared characteristics, complete remission (CR) rates, and relative risks (RRs) of death at 90-day, 1-year, and 3-years in clinical trial patients to patients treated off-trial.Of 867 patients, 58.3% (n = 504) were included in a clinical trial. Accrual rates were similar across age groups (p = 0.55). Patients with poor performance status, comorbidity, therapy-related and secondary AML were less likely to be enrolled in trials. CR rates were 80.2% in trial-patients versus 68.6% in patients treated off- trial. Also, trial-patients had superior survival at 1-year; 72%, vs. 54% (adjusted RR of death 1.28(CI = 1.06-1.54)), and at 3 years; 45% vs. 29% (adjusted RR 1.14(CI = 1.03-1.26)) compared to patients treated off-trial.Despite high accrual rates, patients enrolled in clinical trials had a favorable prognostic profile and a better survival than patients treated off-trial. In conclusion, all trial results should be extrapolated with caution and population-based studies of "real world patients" have a prominent role in examining the prognosis of AML.

Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study.Journal of clinical oncology : official journal of the American Society of Clinical Oncology2015

Abstract

Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age.In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs.Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ? 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ? 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61).Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.

Abstract

Cancer is widely characterized by the sequential acquisition of genetic lesions in a single lineage of cells. Our previous studies have shown that, in acute myeloid leukemia (AML), mutation acquisition occurs in functionally normal hematopoietic stem cells (HSCs). These preleukemic HSCs harbor some, but not all, of the mutations found in the leukemic cells. We report here the identification of patterns of mutation acquisition in human AML. Our findings support a model in which mutations in "landscaping" genes, involved in global chromatin changes such as DNA methylation, histone modification, and chromatin looping, occur early in the evolution of AML, whereas mutations in "proliferative" genes occur late. Additionally, we analyze the persistence of preleukemic mutations in patients in remission and find CD34+ progenitor cells and various mature cells that harbor preleukemic mutations. These findings indicate that preleukemic HSCs can survive induction chemotherapy, identifying these cells as a reservoir for the reevolution of relapsed disease. Finally, through the study of several cases of relapsed AML, we demonstrate various evolutionary patterns for the generation of relapsed disease and show that some of these patterns are consistent with involvement of preleukemic HSCs. These findings provide key insights into the monitoring of minimal residual disease and the identification of therapeutic targets in human AML.

Abstract

Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

Abstract

Monosomal karyotype (MK), defined as 2 or more monosomies, or a single monosomy in the presence of structural abnormalities, has recently been reported as identifying a distinct subset of acute myeloid leukemia (AML) patients with an extremely poor prognosis. In an effort to confirm this observation, we analyzed the prognostic impact of MK in 1344 AML patients between the ages of 16 and 88 years treated on Southwest Oncology Group protocols. MK was found in 176 (13%) patients. The proportion of patients with MK increased with age, being present in 4% of patients age 30 or younger, but in 20% of those over age 60. Ninety-eight percent of MK cases were within the unfavorable cytogenetic risk category and comprised 40% of this group. The complete remission rate in patients with unfavorable cytogenetics without MK was 34% versus 18% with MK (P < .01). The 4-year overall survival of patients with unfavorable cytogenetics but without MK was 13% in contrast to a 4-year survival of only 3% with MK (P < .01). Thus, MK defines a sizeable subset of patients with unfavorable cytogenetics who have a particularly poor prognosis.

Abstract

Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukemia (AML) blasts to chemotherapy. A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)]. However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting ?3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi <6?months following their last induction regimen or with refractory disease. Here, we present results in this poor risk group. This trial included a significant number of patients with poor risk cytogenetics (43%) and poor risk molecular mutations. The response rate was 30% and approximately one-fourth of patients were able to proceed to allogeneic hematopoietic stem cell transplant (HSCT). The median overall survival for patients proceeding to allogeneic HSCT is 27.1 months. Although this trial did not meet criteria for a positive study based on the response rate (p?=?.062), these results are encouraging given the poor risk population and suggest that targeting the cholesterol pathway may have therapeutic benefit in AML.

Abstract

Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML). Through an ex vivo functional screen of 94 cytokines, we identified that the pro-inflammatory cytokine interleukin-1 (IL-1) elicited profound expansion of myeloid progenitors in ?67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1? and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34(+) cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML.

Abstract

While the presence of disseminated intravascular coagulation (DIC) has been implicated in worse clinical outcome in acute leukemia, the relationship between different subtypes of acute leukemia and the clinicopathologic features of DIC has not been systematically well studied.In this study, we retrospectively reviewed 149 cases of newly diagnosed acute leukemia and assessed the utility of evaluating red blood cell morphologic features, and coagulation parameters in determining the presence of DIC as well as differentiating subtypes of acute leukemia.Review of our cohort demonstrates a novel finding, that elevated D-dimer concentrations ?19 000 ng/mL fibrinogen equivalent units (FEU) are a sensitive diagnostic indicator of acute promyelocytic leukemia (APL) with moderate specificity, sensitivity 96%, specificity 92% in acute leukemia subtyping. Similar to other studies, APL showed an increased incidence of DIC (P < 0.01) compared to other subtypes of acute leukemia. Surprisingly, the presence of schistocytes on the peripheral blood smear was not a statistically significant indicator of DIC, sensitivity of 36% and specificity of 89%. Finally, the presence of DIC was not a significant indicator of poorer prognosis amongst all patients with AML.Overall we identify elevated D-dimer concentrations ?19 000 ng/mL FEU are a sensitive indicator of acute promyelocytic leukemia (APL), with a sensitivity of 96% and specificity of 92% in the subtyping of acute leukemias, and that the presence of schistocytes in peripheral blood smears is not a diagnostically sensitive screening test for DIC with a sensitivity of 36%.

Abstract

Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies.

Abstract

Therapy of acute myeloid leukemia in older persons is associated with poor outcomes because of intolerance to intensive therapy, resistant disease and co-morbidities. This multi-center, randomized, open-label, phase-2 trial compared safety and efficacy of three therapeutic strategies in persons ?65 years with newly-diagnosed acute myeloid leukemia: (1) continuous high-dose lenalidomide (N=15); (2) sequential azacitidine and lenalidomide (N=39); and (3) azacitidine (N=34) only. The efficacy endpoint was 1-year survival. Median age was 76 years (range, 66-87 years). Thirteen subjects (15%) had prior myelodysplastic syndrome and 41 (47%), adverse cytogenetics. One-year survival was 21% (95% confidence interval, 0, 43%) with high-dose lenalidomide, 44% (28, 60%) with sequential azacitidine and lenalidomide, and 52% (35, 70%) with azacitidine only. Lenalidomide at a continuous high-dose schedule was poorly-tolerated resulting in a high rate of early-therapy discontinuations. Hazard of death in the 1(st) 4 months was greatest in subjects receiving continuous high-dose lenalidomide; hazards of death thereafter were similar. These data do not favor use of continuous high-dose lenalidomide or sequential lenalidomide and azacitidine over the conventional dose and schedule of azacitidine only in persons aged ?65 years with newly-diagnosed acute myeloid leukemia. The study is registered at ClinicalTrials.gov (NCT01358734).

Abstract

To our knowledge, this multicenter analysis is the first to test and validate (1) the prognostic impact of comorbidities on 1-year mortality after initial therapy of acute myeloid leukemia (AML) and (2) a novel, risk-stratifying composite model incorporating comorbidities, age, and cytogenetic and molecular risks.To accurately estimate risks of mortality by developing and validating a composite model that combines the most significant patient-specific and AML-specific features.This is a retrospective cohort study. A series of comorbidities, including those already incorporated into the hematopoietic cell transplantation-comorbidity index (HCT-CI), were evaluated. Patients were randomly divided into a training set (n?=?733) and a validation set (n?=?367). In the training set, covariates associated with 1-year overall mortality at a significance level of P?.10 constructed a multivariate Cox proportional hazards model in which the impact of each covariate was adjusted for that of all others. Then, the adjusted hazard ratios were used as weights. Performances of models were compared using C statistics for continuous outcomes and area under the curve (AUC) for binary outcomes.Initial therapy for AML.Death within 1 year after initial therapy for AML.A total of 1100 patients, ages 20 to 89 years, were treated for AML between January 1, 2008, and December 31, 2012, at 5 academic institutions specialized in treating AML; 605 (55%) were male, and 495 (45%) were female. In the validation set, the original HCT-CI had better C statistic and AUC estimates compared with the AML comorbidity index for prediction of 1-year mortality. Augmenting the original HCT-CI with 3 independently significant comorbidities, hypoalbuminemia, thrombocytopenia, and high lactate dehydrogenase level, yielded a better C statistic of 0.66 and AUC of 0.69 for 1-year mortality. A composite model comprising augmented HCT-CI, age, and cytogenetic/molecular risks had even better predictive estimates of 0.72 and 0.76, respectively.In this cohort study, comorbidities influenced 1-year survival of patients with AML, and comorbidities are best captured by an augmented HCT-CI. The augmented HCT-CI, age, and cytogenetic/molecular risks could be combined into an AML composite model that could guide treatment decision-making and trial design in AML. Studying physical, cognitive, and social health might further clarify the prognostic role of aging. Targeting comorbidities with interventions alongside specific AML therapy might improve survival.

Abstract

Exclusive of membrane-proximal mutations seen commonly in chronic neutrophilic leukemia (e.g. T618I), functionally defective mutations in the extracellular domain of the granulocyte colony-stimulating factor receptor (CSF3R) have been reported only in severe congenital and idiopathic neutropenia patients. Here we describe the first activating mutation in the fibronectin like type III domain of the extracellular region of CSF3R (W341C) in a leukemia patient. This mutation transformed cells via cysteine-mediated intermolecular disulfide bonds, leading to receptor dimerization. Interestingly, a CSF3R cytoplasmic truncation mutation (W791X) found on the same allele as the extracellular mutation and the expansion of the compound mutation was associated with increased leukocytosis and disease progression of the patient. Notably, the primary patient sample and cells transformed by W341C and W341C/W791X exhibited sensitivity to JAK inhibitors. We further showed that disruption of original cysteine pairs in the CSF3R extracellular domain resulted in either gain- or loss-of-function changes, part of which was attributable to cysteine-mediated dimer formation. This, therefore, represents the first characterization of unpaired cysteines that mediate both gain and loss of function phenotypes. Overall, our results show the structural and functional importance of conserved extracellular cysteine pairs in CSF3R and suggest the necessity for broader screening of CSF3R extracellular domain in leukemia patients.

Abstract

Cancer is the leading cause of death in older adults aged 60 to 79 years. Older patients with good performance status are able to tolerate commonly used treatment modalities as well as younger patients, particularly when adequate supportive care is provided. For older patients who are able to tolerate curative treatment, options include surgery, radiation therapy (RT), chemotherapy, and targeted therapies. RT can be highly effective and well tolerated in carefully selected patients, and advanced age alone should not preclude the use of RT in older patients with cancer. Judicious application of advanced RT techniques that facilitate normal tissue sparing and reduce RT doses to organs at risk are important for all patients, and may help to assuage concerns about the risks of RT in older adults. These NCCN Guidelines Insights focus on the recent updates to the 2016 NCCN Guidelines for Older Adult Oncology specific to the use of RT in the management of older adults with cancer.

Abstract

The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1. The Brd4 inhibitors JQ1 and I-BET-151 also inhibit autophagy and increase NPM1 and HEXIM1 expression. We conclude that the degradation of NPM1 and HEXIM1 through autophagy in certain AML subsets contributes to the activation of the BET pathway in these cells.

Abstract

Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m(2) and intravenous bortezomib at a dose of 1·3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m(2) . Two patients experienced dose-limiting toxicity of mucositis. The most frequent non-haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.

Abstract

The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). We describe a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. Median number of treatment cycles on study was two (range, 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders versus non-responders was 9.8 versus 4.0 months, respectively (HR 0.36, p=0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

Abstract

Recently our group and others have identified DDX41 mutations both as germline and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome and/or acute myeloid leukemia (MDS/AML), suggesting that DDX41 acts as a tumor suppressor. To determine if novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our groups screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine with DDX41 mutations (3%). As previously observed, MDS/AML were the most common malignancies, often of the erythroblastic subtype, and one family displayed early onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains, and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germline DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.

Predictors of early death and survival among children, adolescents and young adults with acute myeloid leukaemia in California, 1988-2011: a population-based study.British journal of haematology2016

Abstract

A better understanding of factors associated with early death and survival among children, adolescents and young adults with acute myeloid leukaemia (AML) may guide health policy aimed at improving outcomes in these patients. We examined trends in early death and survival among 3935 patients aged 0-39 years with de novo AML in California during 1988-2011 and investigated the associations between sociodemographic and selected clinical factors and outcomes. Early death declined from 9·7% in 1988-1995 to 7·1% in 2004-2011 (P = 0·062), and survival improved substantially over time. However, 5-year survival was still only 50% (95% confidence interval 47-53%) even in the most recent treatment period (2004-2011). Overall, the main factors associated with poor outcomes were older age at diagnosis, treatment at hospitals not affiliated with National Cancer Institute-designated cancer centres, and black race/ethnicity. For patients diagnosed during 1996-2011, survival was lower among those who lacked health insurance compared to those with public or private insurance. We conclude that mortality after AML remained strikingly high in California and increased with age. Possible strategies to improve outcomes include wider insurance coverage and treatment at specialized cancer centres.

Abstract

Activation of the IRE1?-XBP1 branch of the unfolded protein response (UPR) has been implicated in multiple types of human cancers, including multiple myeloma (MM). Through an in silico drug discovery approach based on protein-compound virtual docking, we identified the anthracycline antibiotic doxorubicin as an in vitro and in vivo inhibitor of XBP1 activation, a previously unknown activity for this widely utilized cancer chemotherapeutic drug. Through a series of mechanistic and phenotypic studies, we showed that this novel activity of doxorubicin was not due to inhibition of topoisomerase II (Topo II). Consistent with its inhibitory activity on the IRE1?-XBP1 branch of the UPR, doxorubicin displayed more potent cytotoxicity against MM cell lines than other cancer cell lines that have lower basal IRE1?-XBP1 activity. In addition, doxorubicin significantly inhibited XBP1 activation in CD138(+) tumor cells isolated from MM patients. Our findings suggest that the UPR-modulating activity of doxorubicin may be utilized clinically to target IRE1?-XBP1-dependent tumors such as MM.

Abstract

Acute myeloid leukemia (AML) is characterized by a high relapse rate that has been attributed to the quiescence of leukemia stem cells (LSCs), which renders them resistant to chemotherapy. However, this hypothesis is largely supported by indirect evidence and fails to explain the large differences in relapse rates across AML subtypes. To address this, bone marrow aspirates from 41 AML patients and five healthy donors were analyzed by high-dimensional mass cytometry. All patients displayed immunophenotypic and intracellular signaling abnormalities within CD34+CD38low populations and several karyotype and genotype-specific surface marker patterns were identified. The immunophenotypic stem and early progenitor cell populations from patients with clinically favorable core-binding factor AML demonstrated a five-fold higher fraction of cells in S-phase compared to other AML samples. Conversely, LSCs in less clinically favorable FLT3-ITD AML exhibited dramatic reductions in S-phase fraction. Mass cytometry also allowed direct observation of the in vivo effects of cytotoxic chemotherapy.

Abstract

Over half of patients diagnosed with acute myeloid leukemia (AML) are 65 years or older. We examined patient characteristics, treatment patterns, and survival among elderly patients in routine clinical practice. We utilized a retrospective cohort analysis of first primary AML patients in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were diagnosed between January 1, 2000 and December 31, 2009, >66 years, and continuously enrolled in Medicare Part A and B in the year prior to diagnosis. Kaplan-Meier curves and Cox proportional hazards regression assessed overall survival by treatment. There were 3327 (40 %) patients who received chemotherapy within 3 months of diagnosis. Treated patients were more likely younger, male, and married, and less likely to have secondary AML and poor performance indicators and comorbidity score compared to untreated patients. In multivariate survival analysis, treated patients exhibited a significant 33 % lower risk of death compared to untreated patients. Significant survival benefits were noted with receipt of intensive and hypomethylating agent (HMA) therapies compared to no therapy. A survival benefit with allogeneic hematopoietic stem cell transplantation was seen in younger Medicare patients. This real-world study showed that about 60 % of elderly AML patients remain untreated following diagnosis. Use of anti-leukemic therapy was associated with a significant survival benefit in this elderly cohort.

Abstract

Acute myeloid leukemia (AML) is treated with conventional induction chemotherapy shortly after diagnosis for the majority of patients aged ?65 years. A recent report suggested a substantial decline in the early, or 1-month, mortality rate in patients treated on clinical trials over the past 2 decades. It is unknown whether a similar improvement has been observed in the general population.The authors examined the 1-month mortality rate in a large population-based series of 9380 patients with AML who were aged ?65 years and were diagnosed and treated with chemotherapy between 1973 and 2010.A significant decline was observed in the 1-month mortality rate from 18.7% among patients diagnosed from 1973 through 1977 (95% confidence interval [95% CI], 16.4%-21.2%) to 5.8% for those diagnosed between 2008 and 2010 (95% CI, 4.5%-7.6%) (P

Abstract

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

Abstract

Clonal heterogeneity is a hallmark of malignant transformation. In acute myeloid leukemia, acquired cytogenetic abnormalities are important independent predictors of initial response to therapy, remission duration, and overall survival. It remains poorly defined, however, whether the presence of multiple cytogenetically characterized clones affects outcomes in acute myeloid leukemia. The aim of this study was to assess the prognostic impact of cytogenetic clonal heterogeneity in acute myeloid leukemia. This analysis included 1403 newly diagnosed acute myeloid leukemia patients fit for intensive chemotherapy between the ages of 15 and 88 years enrolled on SWOG protocols. The presence of multiple cytogenetic clones was found in 164 (24%) patients with abnormal karyotype. The proportion of patients with clonal heterogeneity increased with age, being present in 20% of patients younger than 40 years, but in 30% of those over age 70 (p=0.03). Clonal heterogeneity was significantly more common in association with unfavorable karyotype. Clonal heterogeneity was associated with decreased response rates and inferior event-free, relapse-free and overall survival and was confirmed as an independent predictor of poor prognosis in multivariable analysis. Subgroup analysis showed that clonal heterogeneity adds prognostic information particularly in the unfavorable karyotype group. Our results confirm the negative prognostic impact of clonal heterogeneity in acute myeloid leukemia patients with abnormal karyotype. (ClinicalTrials.gov Identifiers: NCT014343329; NCT01338974; NCT00899171; NCT1059734; NCT01059734; NCT00899743; NCT0143329, NCT00023777; NCT00085709; NCT01360125; NCT00004217).

Abstract

Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1(R132H) mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models. This sensitization effect was induced by (R)-2-HG-mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. Our findings indicate that IDH1/2 mutation status may identify patients that are likely to respond to pharmacologic BCL-2 inhibition and form the rational basis for combining agents that disrupt ETC activity with ABT-199 in future clinical studies.

Abstract

Blastic plasmacytoid dendritic cell neoplasm is an exceedingly rare hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. Mutations in isocitrate dehydrogenase (IDH) 1 and 2 genes have been discovered in a range of neoplasms including glioma, acute myeloid leukemia, chondrosarcoma, and intrahepatic cholangiocarcinoma. Mutant IDH acquires neomorphic enzymatic activity to generate the oncometabolite d-2-hydroxyglutarate (d-2HG). Here, we describe the first case of an IDH2 R140Q-mutated blastic plasmacytoid dendritic cell neoplasm in a patient with markedly elevated plasma d-2HG. This finding expands the spectrum of neoplasms with increased d-2HG in association with IDH mutation. The roles of IDH mutation and d-2HG in disease pathogenesis and assessment of clinical response are discussed.

Abstract

Intensive chemotherapy with cytarabine and an anthracycline for untreated acute myeloid leukemia (AML) has remained largely unchanged over the past 40 years, despite many large trials examining the choice and dosing of these agents.We will review the major published clinical trials for untreated AML that have established the dosing choice and schedule for intensive therapy, as well as trials for patients not eligible for more intensive therapy. We will also discuss treatment considerations for subgroups of patients.While one or two cycles of anthracycline and cytarabine-based combination regimens remain the standard of care for younger and older patients with AML deemed fit to receive induction chemotherapy, controversy remains regarding the optimal selection and dosing schedule for anthracyclines. Low-intensity regimens, such as low-dose cytarabine and hypomethylating agents, can achieve a complete response even with adverse risk features, and can be used in a fit subset of older patients not eligible for clinical trial or transplant. Incorporation of new targeted agents, such as tyrosine kinase and small-molecule inhibitors, combined with better selection of drugs for unique patient cohorts, will likely be necessary to substantially improve outcomes in AML.

Abstract

High levels of miR-155 are associated with poor outcome in acute myeloid leukemia (AML). In AML, miR-155 is regulated by NF-?B, the activity of which is in part controlled by NEDD8-dependent ubiquitin ligases. We demonstrate that MLN4924, an inhibitor of NEDD8 activating enzyme (NAE) presently being evaluated in clinical trials, decreases binding of NF-?B to the miR-155 promoter and downregulates miR-155 in AML cells. This results in upregulation of the miR-155 targets SHIP1, an inhibitor of the PI3K/Akt pathway, and PU.1, a transcription factor important for myeloid differentiation, leading to monocytic differentiation and apoptosis. Consistent with these results, overexpression of miR-155 diminishes MLN4924-induced antileukemic effects. In vivo, MLN4924 reduces miR-155 expression and prolongs survival of mice engrafted with leukemic cells. Our study demonstrates the potential of miR-155 as a novel therapeutic target in AML via pharmacologic interference with NF-?B-dependent regulatory mechanisms. We show the targeting of this oncogenic microRNA with MLN4924, a compound presently being evaluated in clinical trials in AML. Since high miR-155 levels have been consistently associated with aggressive clinical phenotypes, our work opens new avenues for microRNA-targeting therapeutic approaches to leukemia and cancer patients.Leukemia accepted article preview online, 14 May 2015. doi:10.1038/leu.2015.106.

Abstract

The survival of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor. We performed a retrospective analysis of 40 patients treated with five days of mitoxantrone 8mg/m(2)/day, etoposide 100mg/m(2)/day, and cytarabine 1000mg/m(2)/day (MEC). The complete remission rate was 30% and median remission duration was 11.2 months. Median overall survival was 6.5 months. In univariate analysis, patients in first relapse had improved overall survival compared to ?second relapse (p=0.02). Thirty-day mortality rate was 7.5%. In relapsed or refractory ALL, MEC demonstrated moderate activity, but did not improve survival compared to published salvage chemotherapy regimens.

Abstract

This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 ?g/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579.

Abstract

The NEDD8-activating enzyme (NAE) initiates neddylation, the cascade of post-translational NEDD8 conjugation onto target proteins. MLN4924, a selective NAE inhibitor, has displayed preclinical anti-tumor activity in vitro and in vivo, and promising clinical activity has been reported in patients with refractory hematologic malignancies. Here, we sought to understand the mechanisms of resistance to MLN4924. K562 and U937 leukemia cells were exposed over a 6 month period to MLN4924 and populations of resistant cells (R-K562(MLN), R-U937(MLN)) were selected. R-K562(MLN) and R-U937(MLN) cells contain I310N and Y352H mutations in the NAE catalytic subunit UBA3, respectively. Biochemical analyses indicate that these mutations increase the enzyme's affinity for ATP while decreasing its affinity for NEDD8. These mutations effectively contribute to decreased MLN4924 potency in vitro while providing for sufficient NAE function for leukemia cell survival. Finally, R-K562(MLN) cells showed cross-resistance to other NAE-selective inhibitors, but remained sensitive to a pan-E1 (activating enzyme) inhibitor. Thus, our work provides insight into mechanisms of MLN4924 resistance to facilitate the development of more effective second-generation NAE inhibitors.

Abstract

Chromosome banding analysis is the gold standard method for the identification of recurrent cytogenetic abnormalities in acute myeloid leukaemia (AML). It allows stratification of AML patients into subgroups with distinct responses to therapy and survival. Unfortunately, a variety of issues hamper cytogenetic evaluation in c. 10% of cases [unsuccessful cytogenetics (UC)] and the outcome of these patients is poorly understood. To better define the significance of UC in patients with AML, we compared the baseline characteristics and the prognostic impact of 94 (6%) patients, whose standard metaphase analysis yielded unacceptable results, to the remaining 1403 AML patients with successful cytogenetic analysis treated on successive Southwestern Oncology Group protocols. The incidence of UC increased with age, with peak incidence in patients older than 60 years. These patients had a lower response rate to induction chemotherapy (complete remission rate of 43%) and dismal 5-year survival rates (16%), which was especially poor in patients older than 60 years (<5%). The complete remission and survival rates were similar to those seen in patients with unfavourable karyotype. The early death rate was not increased. These results suggest that UC increases with age and predict for poor outcomes, similar to the outcomes of patients with unfavourable karyotype.

Abstract

Epigenetic therapeutics such as the histone deacetylase inhibitor, vorinostat, and the DNA methyltransferase I inhibitor, azacitidine, enhance gemtuzumab ozogamicin efficacy in vitro. We therefore investigated vorinostat/azacitidine/gemtuzumab ozogamicin in 52 adults aged 50 years or over with acute myeloid leukemia requiring therapy for first relapse (remission duration ? 12 months) or primary refractory disease in a phase I/II trial. Vorinostat and gemtuzumab ozogamicin were escalated step-wise during the phase I portion of the trial. Vorinostat (400 mg/day orally from Days 1-9), azacitidine (75 mg/m(2)/day intravenously or subcutaneously from Days 1-7), and gemtuzumab ozogamicin (3 mg/m(2)/day intravenously on Days 4 and 8) were identified as the maximum tolerated dose. Among the 43 patients treated at this dose, 10 achieved a complete remission and 8 achieved a complete remission with incomplete blood count recovery, for an overall response rate of 41.9% (exact 95% confidence interval (CI): 27.0-57.9%). Four of these 18 patients (2 with complete remission and 2 with complete remission with incomplete blood count recovery) had persistence of minimal residual disease by flow cytometry at the time of best response. Four patients died within 28 days of treatment initiation. Median overall survival for the 18 patients achieving complete remission/complete remission with incomplete blood count recovery was significantly longer than for those 21 patients who failed therapy but lived at least 29 days after treatment initiation (224.5 days (range 70-798) vs. 95 days (range 36-900); P=0.0023). These data indicate that vorinostat/azacitidine/gemtuzumab ozogamicin has activity in this difficult-to-treat acute myeloid leukemia patient subset. (ClinicalTrials.gov: identifier 00895934).

Abstract

Hematopoietic cell transplantation (HCT) provides a life-prolonging or potentially curative treatment option for patients with hematologic malignancies. Given the high transplant-related morbidity, these treatment strategies were initially restricted to younger patients, but are increasingly being used in older adults. The incidence of most hematologic malignancies increases with age; with the aging of the population, the number of potential older candidates for HCT increases. Autologous HCT (auto-HCT) in older patients may confer a slightly increased risk of specific toxicities (such as cardiac toxicities and mucositis) and have modestly lower effectiveness (in the case of lymphoma). However, auto-HCT remains a feasible, safe, and effective therapy for selected older adults with multiple myeloma and lymphoma. Similarly, allogeneic transplant (allo-HCT) is a potential therapeutic option for selected older adults, although fewer data exist on allo-HCT in older patients. Based on currently available data, age alone is not the best predictor of toxicity and outcomes; rather, the comorbidities and functional status of the older patient are likely better predictors of toxicity than chronologic age in both the autologous and allogeneic setting. A comprehensive geriatric assessment (CGA) in older adults being considered for either an auto-HCT or allo-HCT may identify additional problems or geriatric syndromes, which may not be detected during the standard pretransplant evaluation. Further research is needed to establish the utility of CGA in predicting toxicity and to evaluate the quality of survival in older adults undergoing HCT.

Abstract

Cancer is the leading cause of death in older adults aged 60 to 79 years. The biology of certain cancers and responsiveness to therapy changes with the patient's age. Advanced age alone should not preclude the use of effective treatment that could improve quality of life or extend meaningful survival. The challenge of managing older patients with cancer is to assess whether the expected benefits of treatment are superior to the risk in a population with decreased life expectancy and decreased tolerance to stress. These guidelines provide an approach to decision-making in older cancer patients based on comprehensive geriatric assessment and also include diseasespecific issues related to age in the management of some cancer types in older adults.

Abstract

There is growing interest in incorporating routine collection of patient-reported outcomes (PROs) into cancer care. Practicing oncologists are a stakeholder group whose views are not well characterized.We developed an interview guide after literature review and in-depth interviews with leaders in the field. We conducted 45-minute semistructured interviews with a diverse sample of medical oncologists identified through affiliation with the Quality Oncology Practice Initiative or a minority-based Community Clinical Oncology Program until thematic saturation. Multiple analysts independently reviewed and thematically coded verbatim transcripts.Seventeen interviews were conducted with oncologists from 15 states. Emergent themes included variable understanding and experience with PROs. There was enthusiasm for the potential of PROs to improve the efficiency and thoroughness of the patient encounter. Fundamental concerns included information overload, possibility of identifying problems without access to intervention, depersonalization of the physician-patient encounter, cost, and inefficiency. Barriers identified included the need for buy-in from other stakeholders in the practice, lack of appropriate referral resources, staffing needs, and technology concerns. Few identified patient compliance, data sharing/privacy, or medical liability as a major barrier to implementation.Practicing oncologists had variable understanding of the details of PROs but, when introduced to the concept, recognized utility in improving the efficiency and thoroughness of the patient encounter if implemented properly. The time is right to begin pilot testing such measures with community oncologists so they can lend their expertise to national discussions on which measures to use and how best to use them.

Abstract

Due to a national shortage of daunorubicin we evaluated the effects of substituting doxorubicin 1:1 in the induction phase for adult patients with newly diagnosed acute lymphoblastic leukemia (ALL). We identified 10 patients receiving doxorubicin instead of daunorubicin as part of their induction on Cancer and Leukemia Group B (CALGB) 9511 or CALGB10403 and retrospectively compared them to 83 patients who received treatment on the same protocols with daunorubicin. Response rates were similar, independent of anthracycline received, with either CALGB9511 or CALGB10403. In either regimen, doxorubicin resulted in longer absolute neutrophil count (ANC) recovery time and hospitalization. Doxorubicin as part of CALGB9511 resulted in greater than three-fold higher mucositis. Sepsis and death during induction were significantly more frequent in patients who received doxorubicin on CALGB10403. While remission rates were similar, the use of doxorubicin was associated with prolonged neutropenia, higher risk of mucositis, infection and sepsis, and prolonged hospitalization. Higher induction mortality observed with doxorubicin substitution in this analysis needs further study.

Abstract

There are limited treatment options for older patients with acute myeloid leukemia and prognosis of these patients remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older patients with acute myeloid leukemia. Patients ? 60 years of age with untreated acute myeloid leukemia received azacitidine 75 mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 weeks. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Forty-two patients (median age, 74 years) were enrolled with equal distribution according to European LeukemiaNet risk. The overall response rate was 40% (rate of complete remission with or without complete recovery of blood counts = 28%). The median time to complete remission with or without complete recovery of blood counts was 12 weeks, and duration of this status was 28 weeks (range, 4 - >104 weeks). Therapy-related acute myeloid leukemia and a high score on the Hematopoietic Cell Transplantation Comorbidity Index were negative predictors of response. Early death was noted in 17% of patients. Grades ? 3 toxicities were uncommon and most adverse events were gastrointestinal, fatigue and myelosuppression. In conclusion, a sequential combination of azacitidine plus lenalidomide has clinical activity in older patients with acute myeloid leukemia, and further studies of this combination are underway.

Abstract

Multiple myeloma is a hematological neoplasm characterized by the accumulation of clonal plasma cells in the bone marrow. Its frequent relapse following achievement of clinical remissions implicates the existence of therapy-resistant myeloma-initiating cells. To date, results on the identity of myeloma-initiating cells have differed. Here, we prospectively identified a myeloma-initiating population by fractionating and transplanting patient bone marrow cells into human bone-bearing immunocompromised mice. Xenotransplantation of fractionated CD138(+)/CD38(high) cells from 40% of patients (8/20) led to a repopulation of CD19(+)CD38(low) or CD138(+)CD38(+) B-lineage cells in human bone grafts; and these grafts were clonally derived from patient myeloma cells. Meanwhile, CD19(+)CD38(low) xenografts were detected in human bone-bearing mice transplanted with CD19(+)CD38(low/-) B cells from 8 of 22 samples but were not clonally related to patient myeloma cells. Further fractionation and xenotransplantation of CD138(+)CD38(high) cells demonstrated that (CD45(low/-) or CD19(-)) CD38(high)/CD138(+) plasma cells, but not (CD45(high) or CD19(+)) CD38(high)/CD138(+) plasmablasts enrich for myeloma-initiating cells. Quantitative reverse transcription-PCR of two serially transplantable xenografts, which were CD19(-)CD138(+), revealed that they were Pax5 (a B-cell-specific transactivator)-negative. These results suggest that CD19(-)CD45(low/-) fully differentiated plasma cells enrich for long-lived and tumor-initiating cells whereas B cells or plasmablasts do not.

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening inflammatory disorder characterized by uncontrolled proliferation and activation of histiocytes with phagocytosis of normal hematopoietic cells. A 41-year-old woman, 19 weeks pregnant with twins, and a history of Still's disease, presented with rash, fever, and headache. Laboratory studies revealed transaminitis, hyperbilirubinemia, and eventually severe neutropenia as well as elevations in ferritin, lactate dehydrogenase, and C-reactive protein. A bone marrow biopsy confirmed HLH. She declined standard HLH-treatment but responded well to high-dose corticosteroids. Her blood counts remained stable following corticosteroid taper, and she delivered healthy twin girls at 30-week gestation. Few cases of HLH during pregnancy have been reported. In some cases, the condition has proved fatal. Therefore recognizing signs and symptoms of HLH is essential to avoid treatment delay. In our case, high-dose corticosteroids alone were a safe and effective therapy for the mother and fetuses resulting in long-term disease control.

Abstract

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma. These include the addition of regimens containing novel agents as primary and salvage therapy options, inclusion of the updated summary of response categories and criteria from the sixth international workshop on Waldenström's Macroglobulinemia, and a section on management of peripheral neuropathy in the accompanying discussion.

Abstract

We investigated the prognostic impact of absolute lymphocyte count (ALC) following induction chemotherapy in newly diagnosed adult acute lymphoblastic leukemia (ALL). Patients with ALC ?350 cells/?L at day 28 had a median overall survival (OS) of 47.4 months when compared with 17.6 months for those with an ALC <350 cells/?L (HR = 1.98, P = 0.007). Among patients who achieved a complete remission, median event-free survival (EFS) for those with ALC ?350 cells/?L on day 28 was 42.1 months when compared with 13.9 months in those with ALC <350 cells/?L (HR = 2.08, P = 0.006). In multivariable analysis, the ALC on day 28 (<350 cells/?L vs. ?350 cells/?L, P ? .0004 for OS and EFS) along with WBC at diagnosis (?6.0 or >30.0 K/?L vs. >6.0-30.0 K/?L, P ? 0.002 for OS and EFS) and cytogenetics (abnormal vs. normal, P = 0.002 for OS and P = 0.02 for EFS) were independent prognostic factors of both OS and EFS. Combining these three factors segregates patients in three well-defined risk groups. These data suggest that ALC can be used in combination with other prognostic features to better predict outcome and that targeting the immune system to improve ALC may be a worthwhile strategy in ALL.

Abstract

Obesity increases the risk of treatment-related complications and reduces survival in children with acute myeloid leukemia. Little is known about the impact of obesity on the outcome of adult patients with acute myeloid leukemia.We compared the baseline characteristics and effect on treatment and survival in 1,974 previously untreated adult patients with acute myeloid leukemia undergoing treatment, according to international classification of body-mass index.The median body-mass index was 26.7 (15.5-61) and 63% of patients were overweight/obese. After adjustment for other confounders, such as age, gender, performance status, karyotype, white blood cell, platelet and peripheral blast counts, obese patients had better complete remission rates (P=0.0046), lower rates of resistant disease (P=0.038) but similar rates of survival and severe adverse events.In the treatment of acute myeloid leukemia in adults, obesity was associated with increased response rates and no apparent increase in toxicity. Obesity should not, therefore, be a criterion for excluding patients from aggressive therapy.

Abstract

Although complete remissions can be achieved in most patients younger than 60 years of age with untreated acute myeloid leukemia (AML), only 30-40 % of patients remain long-term survivors. Furthermore, long-term survivors represent only 10-15 % of all AML patients older than 60 years of age and <10 % of all patients with relapsed AML. The development of new treatments for AML is therefore needed. Novel therapies should target specific mechanisms and pathways implicated in the development and maintenance of AML, should strive to have better tolerability than conventional combination chemotherapy, be associated with improved quality of life and minimize utilization of health care resources. In this manuscript, we discuss the role of epigenetic regulators and immunomodulatory agents in the treatment of AML. Also, we review the data on inhibitors of protein homeostasis and its synergistic effect to DNA methyltransferase inhibitors, the potential role for inhibitors of heat shock proteins and the mitotic machinery and a novel formulation of conventional chemotherapeutic agents given at a fixed molar concentration. Finally, we briefly share our views on optimal clinical trial design and patient selection for future studies in AML.

Abstract

Karyotype allows for stratification of outcomes in acute myeloid leukemia (AML) patients. Previous data suggested that the presence of residual normal cells improved the prognosis in patients with monosomy 7. The Southwest Oncology Group (SWOG) reported the impact of residual normal metaphases in AML patients with monosomal karyotype (MK) and found a similar relationship. We determined the influence of residual normal metaphases in patients with core binding factor (CBF) AML.The presence and total number of normal and abnormal metaphases were tallied for patients with CBF AML treated in 10 consecutive SWOG trials and used as a variable to determine the effect on complete remission, refractory disease, and overall survival (OS) rates.Among 113 CBF AML patients, median age of diagnosis was 45 years (range, 18-77 years), and median OS was 4 years (CI-2 years-not reached). Patients with inv(16) and no normal metaphases had improved OS compared with those with 1+ normal metaphases (P = .00005), whereas no difference was noted for patients with t(8;21). Multivariate analysis demonstrated that having cells with a normal karyotype had a negative impact on survival (HR, 2.11; 95% CI, 1.09-4.08; P = .026). This shorter survival was a consequence of a higher rate of refractory disease in older patients (OR, 1.03; 95% CI, 0.9998-1.06; P = .05) and in those with normal metaphases (HR, 1.26 95% CI, 1.04-1.51; P = .02).In patients with CBF AML, the presence of cells with normal metaphases and increasing age negatively affect the prognosis, especially in patients with inv(16).

Abstract

A 19-year-old male patient presented with intermittent high fever and left cervical lymphadenopathy. The lymph node biopsy findings were interpreted as "Epstein-Barr virus (EBV)-associated lymphoproliferative disorder consistent with infectious mononucleosis." No molecular studies were performed at that time. The patient was followed without treatment. Five months later, the patient again presented with fever, lymphadenopathy, and splenomegaly. The lymph node biopsy showed features of a diffuse large B-cell lymphoma. Molecular studies on this lymph node biopsy showed a clonal EBV population, although polymerase chain reaction studies failed to reveal a clonal B-cell or T-cell population. A concurrent bone marrow biopsy showed features consistent with hemophagocytic syndrome. He had elevated ferritin, soluble interleukin-2 receptors and persistent EBV viremia. The patient responded to Rituxan for a short period with undetectable EBV levels. Subsequent right cervical lymph node, liver, and jejunal biopsies showed involvement by diffuse large B-cell lymphoma and the patient expired soon thereafter.

Abstract

In acute myeloid leukemia (AML), cytogenetic abnormalities are present in more than half of patients and these chromosomal alterations are critical factors that determine response to chemotherapy and survival.

Abstract

Temozolomide sensitivity is determined by methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter. This study assessed whether the temozolomide dose can be tailored by MGMT promoter status and whether protracted, low-dose temozolomide can "prime" blasts in patients with unmethylated MGMT (unMGMT). Elderly patients with high-risk AML were stratified by MGMT methylation. Patients with methylated MGMT (mMGMT) received temozolomide 200 mg/m(2) orally for 7 days every 4 weeks, while patients with unMGMT received temozolomide 100 mg/m(2) orally for 14 days followed by 200 mg/m(2) orally for 7 days every 6weeks. Of 36 patients (median age, 75 years), 31 (86%) had an unMGMT promoter. Overall response rate for the entire cohort was 36%. Patients with mMGMT and unMGMT had similar response rates (40% vs. 29%). Median duration of response and overall survival (OS) among responders were 29 and 35 weeks, respectively. Induction deaths (ID) occurred in 25% of patients, mostly caused by disease progression. Hematological toxicities were the most common adverse event. Toxicities were similar between patients on conventional versus protracted schedules. High HCT-CI scores were predictive of lower CR rate, higher ID, and shorter OS, while bone marrow blast count <50% at screening predicted for improved responses. Temozolomide, dosed according to MGMT methylation status, demonstrated modest clinical activity in elderly patients with AML, especially in those presenting with fewer comorbidities and low disease burden. The trial was registered on www.ClinicalTrials.gov as #NCT00611247.

Abstract

Early mortality in acute promyelocytic leukemia has been reported to occur in less than 10% of patients treated in clinical trials. This study reports the incidence and clinical features of acute promyelocytic leukemia patients treated at Stanford Hospital, CA, USA since March 1997, focusing on early mortality. We show that the risk of early death in acute promyelocytic leukemia patients is higher than previously reported. In a cohort of 70 patients who received induction therapy at Stanford Hospital, 19% and 26% died within seven and 30 days of admission, respectively. High early mortality was not limited to our institution as evaluation of the Surveillance, Epidemiology and End Results Database demonstrated that 30-day mortality for acute promyelocytic leukemia averaged 20% from 1977-2007 and did not improve significantly over this interval. Our findings show that early death is now the greatest contributor to treatment failure in this otherwise highly curable form of leukemia.

Abstract

This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6-65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.

Abstract

Cytogenetic analysis at diagnosis is one of the most significant prognostic factors in acute myeloid leukemia (AML). AML patients with unfavorable-risk cytogenetic abnormalities account for 16-30% of younger adult patients and have poor response to standard treatment, with only 32-55% achieving a complete response. Overall survival is also extremely poor with only 5-12% patients alive at 5-10 years after diagnosis. Owing to the poor response in this subset of patients, risk-adapted treatment has been investigated. Allogeneic stem cell transplant has been shown to provide a survival benefit in patients with unfavorable-risk cytogenetic abnormalities in complement receptor 1. Other risk-adapted treatment strategies, such as reduced-intensity conditioning regimens prior to allogeneic stem cell transplant for older patients with AML, have also shown some survival benefit, without increasing treatment-related toxicities. Risk-stratification models that include cytogenetic abnormalities, as well as other molecular markers, are being developed to allow for individualized risk-adapted treatment for patients with AML. Prospective multicenter trials will be needed to validate these prognostic models.

Abstract

The majority of patients with acute myeloid leukaemia (AML) are elderly. Advancements in supportive care and regimen intensification have resulted in improvements in clinical outcomes for younger AML patients, but analogous improvements in older patients have not been realized. While outcomes are compromised by increased comorbidities and susceptibility to toxicity from therapy, it is now recognized that elderly AML represents a biologically distinct disease that is more aggressive and less responsive to therapy. Some patients tolerate and benefit from intensive remission-induction approaches, while others are best managed with less aggressive strategies. The challenge is to differentiate these groups based on host-related and biological features, in order to maximize the therapeutic benefit and minimize toxicity. As more is understood about the complicated pathogenesis and molecular basis of AML, there are more opportunities to develop and test targeted therapies. Elderly patients, with their narrow therapeutic window, are well positioned to derive a benefit from these novel agents, and therefore, despite a difficult past, there are reasons to be optimistic about the future of elderly AML.

Abstract

The NEDD8 (neural precursor cell-expressed developmentally downregulated 8) conjugation pathway regulates the post-translational modification of oncogenic proteins. This pathway has important potential for cancer therapeutics. Several proteins vital in cancer biology are regulated by protein neddylation. These observations led to the development of a small molecule inhibitor that disrupts protein neddylation and leads to cancer cell death and important activity in early phase clinical trials.This review provides an extensive coverage of cellular protein homeostasis with particular emphasis on the NEDD8 conjugation pathway. Insights into a new investigational drug that specifically disrupts the NEDD8 pathway are discussed. The clinical data for this agent are also updated.Neddylation controls key cellular pathways found to be dysregulated in many cancers. Protein neddylation is a relatively under-explored pathway for pharmacologic inhibition in cancer. Selective disruption of this pathway has demonstrated clinical activity in patients with myeloid neoplasms and is worth exploring further in combination with other anti-leukemia agents.

Abstract

Hematopoietic stem cells are larger in size than other cells present in bone marrow, with the exception of monocytes. This distinguishing characteristic can be used to separate them from a whole-marrow sample. A microfluidic device was fabricated using an integrated membrane that is porous at defined areas. This allows for simultaneous valving and filtering functionality, which is crucial for preventing irreversible clogging. This device, as well as a separation procedure, was optimized in this work to enrich hematopoietic progenitor cells from diluted bone marrow of leukemia patients without any additional sample preparation. An enrichment of up to 98% was achieved with this method and the process was scaled up to 17.2 ?L min(-1) of processed sample. Additionally, stem cells were stained with specific antibodies for further analysis. Using a custom-made computer program, the filter was scanned to characterize and quantify cells based on fluorescence. The results were evaluated by comparing them against the results obtained from flow cytometry, confocal microscopy, and Coulter counting.

Abstract

Plasma cell leukemia (PCL) is a rare and aggressive plasma cell dyscrasia. Patients with PCL have a very poor prognosis with median survival measured in months. PCL can present de novo or following a prodrome of plasma cell myeloma. Patients with PCL tend to present with aggressive clinical features, such as extramedullary disease, bone marrow failure, advanced stage disease and expression of distinct immunophenotypic markers, such as lack of CD56 and presence of CD20. Historically, the treatment of PCL has primarily been palliative, with only a small minority of patients achieving a durable remission. The impact of newer agents, such as bortezomib and lenalidomide, in conjunction with autologous and allogeneic stem cell transplantation is uncertain, but emerging data suggest that use of these modalities may help improve the poor prognosis of patients with PCL.

Abstract

Immunophenotypic identification of myeloid specific antigens is an important diagnostic tool in the management of patients with acute myeloid leukemia (AML). These antigens allow determination of cell of origin and degree of differentiation of leukemia blasts. AML with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a relatively rare subtype of AML. The immunophenotypic characteristics of inv(3) AML patients are somewhat limited. We identified 14 new cases of hematological disorders with increased myeloid blasts carrying inv(3)(q21q26.2)/t(3;3)(q21;q26.2). Also, we identified another 13 cases previously published in the literature, where the immunophenotype of inv(3)(q21q26.2) was documented. As a group, patients with AML with inv(3)(q21q26.2) had high levels of early myeloid (CD13, CD33, CD117 and MPO) and uncommitted markers (CD34, HLA-DR and CD56) and a high rate of monosomy 7 in addition to the inv(3)(q21q26.2). Differential karyotype and expression of certain antigens were noted in patients with de novo AML with inv(3)(q21q26.2) vs. those with inv(3)(q21q26.2)-containing blasts.

Abstract

Plasma cell leukemia (PCL) is a rare lymphoproliferative disorder considered to be a variant of multiple myeloma. It is an aggressive disease with a poor clinical response to standard chemotherapeutic agents.A novel regimen consisting of bortezomib, doxorubicin, and dexamethasone is currently under active evaluation for the treatment of multiple myeloma. We employed this combination as front-line chemoinduction therapy for a case of primary PCL.Complete remission was achieved with rapid normalization of hematologic parameters. The combination of bortezomib, doxorubicin and dexamethasone demonstrates promise in the treatment of PCL.

Abstract

Imatinib mesylate (IM) is the standard first-line treatment for patients with chronic myeloid leukemia (CML). Surprisingly, 2-15% of patients achieving a complete cytogenetic response develop cytogenetic abnormalities in Philadelphia (Ph)-negative cells. Following hematopoietic stem cell transplantation (HSCT), IM induces complete molecular responses (CMR) in approximately 70% patients with relapsed CML, and no IM-related cytogenetic abnormalities in Ph-negative donor-derived cells have been described after HSCT. We report a 56-year-old female who presented with a relapse from CML in September 2002. She had received a matched related HSCT for CML in chronic phase. Donor lymphocyte infusion was given 3 years post-HSCT for a relapse. Sustained CMR was achieved within 3 months of initiation of IM. In October 2005, routine evaluation demonstrated continuous CMR, full male donor engraftment and an inv (11) on donor cells. Evaluation of the donor demonstrated no dysplasia or cytogenetic abnormalities. This observation reinforces the possibility that IM therapy may be casually linked to the phenomenon of secondary cytogenetic changes in diploid cells.

Abstract

A common point mutation in the JAK2 tyrosine kinase leads to constitutive hematopoietic growth factor receptor signaling and was recently described in many patients with myeloproliferative disorders (MPDs). However, this JAK2 mutation is present in only a subset (35-50%) of patients with essential thrombocythemia (ET). Thus, the proliferative signals responsible for MPDs in the absence of JAK2 mutations remain largely unknown. Despite intriguing pre-clinical data, where transgenic mice overexpressing FLT3-ITD developed a MPD resembling ET, none of the patient samples from ET patients who were JAK2(V617F)-negative demonstrated the presence of activating mutations in the FLT3 receptor.

Abstract

The clinical characteristics and outcome of 15 patients with acute myelogenous leukemia (AML) who experienced relapse at least 5 years after induction of complete remission (very late-relapse AML) are described. This subgroup represented 3% of all relapsed patients seen at this institution over the same time period. There were eight males in this cohort and the median age at diagnosis was 48 years (range 13 - 77 years). Nine patients had M4/M5 French - American - British (FAB) classification subtype and most had intermediate risk cytogenetics. The median duration of first complete remission (CR-1) was 9 years (range 5.2 - 11.5 years). Thirteen patients (86%) achieved CR-2 with reinduction therapy. The 5-year relapse-free survival and overall survival rates of this cohort were 59% and 51%, respectively. We conclude that very late-relapse AML is a rare event, and that reinduction in these patients is associated with very high CR rates and a potential cure fraction.

Abstract

Transfusion-related acute lung injury (TRALI) is an uncommon life-threatening complication of hemotherapy. It is hypothesized to be the result of two independent insults: the first related to the clinical status of the patient and the second to the infusion of biologic response modifiers within blood components. We present a case of TRALI in a patient who received high-dose Interleukin-2 (IL-2) as treatment for metastatic renal cell carcinoma, where IL-2 is speculated to have been the first insult and transfusion of platelet concentrate the second. This is the first reported case of TRALI complicating treatment with high-dose immunotherapy.